Compounds which inhibit cPLA2 and a process for making those compounds have been disclosed in U.S. patent application Ser. No. 10/302636 filed Nov. 22, 2002, the disclosure of which is incorporated by reference herein. These compounds are useful for a variety of purposes, including the relief of pain and inflammation. In order to bring a drug to market, it is necessary to have an economically feasible process for making the compound. Often, a process that works in the laboratory is not practical from a commercial standpoint. It would be desirable to have a relatively inexpensive and efficient method for making at least some of the aforesaid compounds.
A method for preparing tetrahydropyrido[2,3-d]pyrimidines functionalized at the 5-posiiton starting from acyclic aldehydes is taught by Watson in Synthetic Communications, 28(10), 1897-1905 (1998).
Appleton, et al., in Tetrahedron Lett. 1993, 34, 1529, teach reductive C-3 alkylation of 3-unsubstituted indoles to produce C-3 functionalized indoles, especially 3-(arylmethyl)indoles and 3-(heteroarylmethyl)indoles. In the reference reaction, the initial indole is reacted with an aldehyde or ketone using triethylsilane and trifluoroacetic acid.
A process that includes the coupling of a 2-amino-4,6-dichloropyrimidine with but-3-ynylamine to form an N-pyrimidinyl-but-3-ynylamine, which is then coupled with a 4-substituted iodophenyl compound is disclosed by Taylor, et al., in J. Org. Chem., 57, 3218-3225 (1992). The reaction of the pyrimidylbutynylamine and the iodophenyl compound preserves the triple bond and is carried out in the presence of PdCl2, PPh3 and CuI. In the reference process, hydrogenation of the triple bond is carried out subsequently.
A method for synthesizing N-but-3-ynylphthalimide is taught by Hoffmann, et al., J. Med. Chem., 18(3), 278-284 (1975). In this method, phthalic acid anhydride is reacted with 4-amino-1-butyne in glacial acetic acid to produce the target compound. Iyer et al., J. Am. Chem. Soc., 109, 2759-2770(1987), provide a synthetic method using a Mitsunobo reaction.
Ezquerra, et al., J. Org. Chem., 61(17), 5804-5812 (1996), have described the formation of an indole by iodinating a substituted aniline followed by reaction with (trimethylsilyl)ethyne in the presence of Pd(PPh3)2Cl2, CuI and triethylamine to form a [(trimethylsilyl)ethynyl]aniline. This reaction follows the general theme for synthesizing arylacetylenes taught earlier by Sonogashira, et al., Tetrahedron Letters, 50, 4467-4470 (1975).
Xiao, et al., J. Org. Chem., 64, 9646-9652 (1999), have described a preparation for 2-iodoaniline in which a 4-substituted aniline is reacted with iodine in an aqueous sodium bicarbonate solution. The authors also describe using 2-iodoaniline in the synthesis of other compounds.